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Invasive fetal surgery – A medical and ethical challenge of our time

 

Radu Vladareanu¹,², Vlad Zamfirescu²
¹Obstetrics and Gynecology , Carol Davila University of Medicine and Pharmacy
²Obstetrics and Gynecology, Elias Emergency University Hospital, 
Bucharest Romania

 

Correspondence 

Radu Vladareanu M.D. PhD
Professor and Chairman Obstetrics and Gynecology
Elias University Hospital, Carol Davila University of Medicine, Bucharest, ROMANIA
Mobile: +40.722.351.081 / Tel/Fax:+40.21.316.16.40
E-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.  

 

The diagnosis and treatment of congenital anomalies before birth is evolving as a new form of medical care. The benefit of fetal intervention lies in the ability to treat pathological processes at an early stage of development, thereby preventing fetal demise or arresting the progression of disease to a more deleterious difficult-to-treat state.

Fetal surgery was born of clinical necessity. Observations by pediatric surgeons and neonatologists of neonates that were born with irreversible organ damage led to the conclusion that one possible approach to prevent this alteration of developmental physiology, was fetal surgical intervention. This led to experimental validation of the pathophysiology of specific fetal defects in animal models and to the development of techniques for their prenatal surgical correction. The demonstration in animal models that the correction of an anatomical defect could reverse the associated pathophysiology led to the first systematic application of fetal surgery at the University of California, San Francisco, in the early 1980s. Since that time, fetal surgery has been applied in only a few centers and has remained relatively limited in scope. Nevertheless, there has been a dramatic improvement in our ability to diagnose, select and safely operate on an expanding number of fetal anomalies. The purpose of this article is to briefly summarize the present status of fetal surgery and to speculate about what may be in store for the future. Inherent in such an effort is a definition of what constitutes fetal surgery. In this discussion we will take considerable latitude with the definition of what constitutes fetal surgery in the future, as it is my belief that technological progress in a number of areas will result in dramatic changes in the practice and perception of fetal surgery ( fig.1) [1].

It is widely accepted that the use of ultrasonography has dramatically changed the obstetrical practice worldwide. As the technology of ultrasound equipment has become more sophisticated, the capability of both diagnostic and theraputic procedures increased enormously. More over, the growing experience and the understanding of pathophysiologic changes both duri and ng normal fetal life and in cases of structural abnormal fetuses have given us the possibility of planning and performing different interventions for early diagnosis and therapy.

The availability of high-resolution ultrasound imaging and aneuploidy screening programs has made the unborn child a true patient. Until recently, termination of pregnancy or selec- tive termination of an affected fetus was the option offered to the parents, when a congenital anomaly was diagnosed. Because of our better understanding of fetal physiology and pathology, and the technological improvements implemented during the last decade, many experts in fetal medicine tried to correct the process of a developmental abnormality, early enough in order to prevent a permanent damage to the fetus [2].

When fetal malformations, genetic diseases, or in utero acquired conditions are suspected, patients are referred to tertiary care units with more specialized skills, technical equipment, experience, and multidisciplinary counselors to define potential options. In some cases, intervention before birth may be desirable, which often does not require direct access to the fetus— for example, transplacental administration of pharmacologic agents for cardiac arrhythmias or antibiotics in case of fetal infection. Other conditions can be treated only by invasive access to fetus. In utero transfusion of a hydropic fetus to treat the anemia of Rh isoimmunization, first described in 1961, was probably the first successful invasive therapeutic procedure. Today, blood transfusion through the umbilical cord, intrahepatic vein, or (exceptionally) directly into the fetal heart is widely offered, with good fetal and longterm outcome when procedures are done by experienced operators.

Some conditions are amenable to surgical correction, and in the majority of cases this is best done after birth. Occasionally, prenatal surgery is required to save the life of the fetus or to prevent permanent organ damage. This can be achieved by correcting the malformation, by arresting the progression of the disease, or by treating some of the immediately life-threatening effects of the condition, delaying more definitive repair until after birth.  Because of the potential complications, the risks and benefits of the intervention must be weighed against each other.

 

invasive fetal surgery 1 invasive fetal surgery 2
Figure 1: Time line for future events in fetal intervention Figure. 2: Future technologies and their role in fetal intervention for anatomical and genetic fetal abnormalities [4] 

 The criteria and indications for fetal surgery endorsed by the International Fetal Medicine and Surgery Society (IFMSS), are:  

  •  Accurate diagnosis and staging possible, with exclusion of associated anomalies.
  • Natural history of the disease is documented, and prognosis established.
  • Currently no effective postnatal therapy. 8 In utero surgery proved feasible in animal models, reversing deleterious effects of the condition.
  • Interventions performed in specialized multidisciplinary fetal treatment centers with strict protocols and approval of the local ethics committee and with informed consent of the mother or parents ( fig. 2) [3].

Open fetal surgery

Open fetal surgery is a complex enterprise that should be undertaken only in centers staffed with skilled personnel. Fetal surgery is a specialized technique that requires a multidisciplinary approach, involving pediatric surgeons, perinatal obstetricians, sonographers, echocardiographers, neonatologists, intensive care specialists, geneticists, ethicists, and neonatal and obstetric nurses. Fetal surgery typically involves opening the gravid uterus (with either a traditional Cesarean surgical incision or through single or multiple fetoscopic port incisions), surgically correcting a fetal abnormality, returning the fetus to the uterus, and restoring uterine closure [6].

Because of the high incidence of preterm labor, prophylactic (preoperative and postoperative) tocolysis is essential, using for instance indomethacin or nifedipine. Large-bore venous access is established, but fluid administration is conservative and meticulously managed to reduce the risk of pulmonary edema, which occurs frequently with certain tocolytics. Open surgical procedures are typically performed under general endotracheal anesthesia, taking advantage of the myorelaxant and uterine contraction suppression qualities of halogenated anesthetic gases. The uterus is exposed by a large laparotomy and opened with specially designed, resorbable Lactomer surgical staples to prevent intraoperative maternal hemorrhage. Location of the uterine incision depends largely on placental position, as determined by sterile ultrasound. The fetus is partially exposed and sometimes exteriorized and monitored while the procedure is performed using ultrasound, pulse oximetry, or direct fetal electrocardiography [5]. Additional analgesics, atropine, and pancuronium or vecuronium are given to the fetus to suppress the fetal stress response, bradycardia, as well as to immobilize it. The fetus is kept warm through the use of intrauterine infusion of Ringer’s lactate at body temperature, and intrauterine volume and pressure are maintained as close as possible to physiologic levels. After completion of the fetal portion of the procedure, the uterus is closed in two layers with resorbable sutures, amniotic fluid volume is restored, and intra-amniotic antibiotics are administered. The hysterotomy is covered with an omental flap. Postoperatively, the patient is treated in the intensive care unit and given aggressive tocolysis with magnesium sulfate and, when required, additional agents. Complications of open fetal surgery include preterm contractions, maternal morbidity from tocolysis, rupture of membranes, and fetal distress. Preoperatively, comprehensive counseling should include discussion of complications such as chorioamnionitis, fetal demise, tocolytic side effects, and need for future cesarean deliveries. However, maternal safety has increased in the few centers skilled in open fetal procedures, with fewer intensive care unit admissions, blood transfusions, and uterine ruptures [7].

Indications and rationales for in utero surgery on the fetus, placenta, cord, or membranes

Surgery on the fetus

Congenital diaphragmatic hernia:  

  • pulmonary hypoplasia and anatomic substrate for pulmo- nary hypertension → reversal of pulmonary hypoplasia and reduction in degree of pulmonary hypertension; repair of actual defect delayed until after birth.

Lower urinary tract obstruction:

  • progressive renal damage by obstructive uropathy, pul- monary hypoplasia by oligohydramnios → prevention of renal failure and pulmonary hypoplasia by anatomic correction or urinary deviation.

Sacrococcygeal teratoma:

  • high-output cardiac failure by arteriovenous shunting and/ or bleeding → reduction of functional impact of the tumor by its ablation or (part of ) its vasculature
  • direct anatomic effects of the tumoral mass → reduction of anatomic effects by draining cysts or bladder
  • polyhydramnios-related preterm labor → amnioreduction to prevent obstetric complications.

Thoracic space-occupying lesions:

  • pulmonary hypoplasia (space-occupying mass) → creating space for lung development
  • hydrops from impaired venous return (mediastinal com- pression) → reverse process of cardiac failure

Neural tube defects: 

  • damage to exposed neural tube → prevention of exposure of the spinal cord to amniotic fluid 
  • chronic cerebrospinal fl uid (CSF) leak, leading to Arnold- Chiari malformation and hydrocephalus → restoration of CSF pressure to correct Arnold-Chiari malformation

Cardiac malformations:

  • critical lesions causing irreversible hypoplasia or damage to developing heart → reverse process by anatomic correction of restrictive pathology

Surgery on the Placenta, Cord, or Membranes

Chorioangioma:

  • high-output cardiac failure from arteriovenous shunting, effects of polyhydramnios → reversal of process of cardiac failure and hydrops fetoplacentalis by ablation or reduction of flow

Amniotic bands:

  • progressive constrictions causing irreversible neurologic or vascular damage → prevention of amniotic band syndrome leading to deformities and function loss Abnormal monochorionic twinning: twin-to-twin transfusion:
  • intertwin transfusion leads to oligohydramnios, polyhydramnios sequence, hemodynamic changes; preterm labor and rupture of the membranes; in utero damage to brain, heart, or other organs, In utero fetal death may cause damage to co-twin → arrest intertwin transfusion, prevent or reverse cardiac failure and/or neurologic damage,including at the time of in utero death; prolongation of gestation

Fetus acardiacus and discordant anomalies:

  • cardiac failure of pump twin and consequences of poly- hydramnios, serious anomaly raises question for termination of pregnancy or selective feticide → selective feticide: to arrest parasitic relationship,to prevent consequences of in utero fetal demise, to avoid termination of the entire pregnancy

Exit procedure

Advanced fetal medicine units require less knowledge of open uterine surgery, because the peripartum EXIT (ex utero intrapartum treatment) procedure is increasingly used for selected fetal conditions. The purpose of the EXIT procedure is typically to establish functional and reliable fetal airway control while keeping the fetus attached to the uteroplacental circulation. This is accomplished by delivering only a portion of the fetus through a hysterotomy incision ( fig 3,4). To permit ample time to perform a potentially complex fetal airway procedure, EXIT is done under maximal uterine relaxation, and thus the maternal risks of this procedure are mainly hemorrhagic. Because of the complex interactions necessary between anesthesiology, obstetrics, and pediatrics personnel, EXIT procedures require significant advance preparation, with roles preassigned to the many physicians and nurses involved. Drills and rehearsals for EXIT, as well as experience, enhance the safety and efficacy of the procedure.

During the EXIT procedure, the goals are: to achieve a state of uterine hypotonia to maintain the uteroplacental circulation using deep general anesthesia, to preserve uterine volume to prevent placental abruption, to reach a deep plane of maternal anesthesia but maintain normal maternal blood pressure, achieve a surgical level of fetal anesthesia without cardiac depression.

The number of indications for EXIT has increased:

  • Reversal of tracheal occlusion
  • Giant fetal neck mass
  • EXIT-to-ECMO (ECMO, extracorporeal membrane oxygen- ation)
  • Resection of CCAM (congenital cystic adenomatoid malfor- mation)
  • Unilateral pulmonary agenesis
  • Conjoined twins 8 CHAOS (Congenital high airway obstruction syndrome)
  • Overall [8]

Fetoscopy

Fetoscopic procedures are minimally invasive interventions that can be considered as a cross between ultrasound-guided and formal surgical procedures. The surgeons involved may be fetal medicine specialists or pediatric surgeons, largely depending on local expertise. Fetoscopy must be organized so that the surgical team can see simultaneously both the ultrasound and the fetoscopic image. Embryoscopy and fetoscopy are invasive techniques for direct transuterine visualization of the embryo and the fetus. Embryoscopy is a term that is appropriate only before 12 weeks of gestation while fetoscopy may be used for procedures at a later gestational age. Despite the minimally invasive nature of fetoscopy, it continues to be associated with iatrogenic preterm premature rupture of the membranes (pPROM). Fetoscopy can diagnose Duchenne muscular dystrophy by fetal muscle biopsies. Thera- peutic fetoscopy is used in: diaphragmatic hernia, sacrococcygeal teratoma, amniotic band syndrome, myelomeningocele, twin-twin transfusion syndrome [10]. 

Interventional fetal Cardiology

In Congenital heart Defects (CHD)

There are a variety of cardiac defects that can be considered to be candidates for fetal intervention. The predominant defects include severe aortic stenosis with evolving hypoplastic left heart syndrome, critical stenosis or atresia of the pulmonary valve with intact ventricular septum with evolving hypoplastic right ventricle or heart failure and hypoplastic left heart syndrome with intact or restrictive atrial septum and thus impaired pulmonary venous return. In all these cases, early diagnosis and referral of patients who are to be considered for a fetal intervention procedure is imperative.

 

invasive fetal surgery 3 invasive fetal surgery 4
Figure 3. A view of the EXIT procedure with the fetal head and left arm out of the uterus. The red rubber catheter is providing the amnioinfusion Figure 4. At the completion of the EXIT procedure, the tracheostomy is secured in place on the left side of the neck. The fetus was then delivered and the umbilical cord was cut [9]

Fetal cardiac intervention includes the process of identifying fetuses who are candidates for such a procedure and taking the steps to make treatment available to them. Most patients with CHD can undergo postnatal surgery with low (<5%) mortality and good quality of life in survivors. But when this is not the case and the abnormal cardiac anatomy leads to progressive myocardial and pulmonary damage during the pregnancy, which will ultimately preclude effective postnatal treatment, timely fetal intervention can be lifesaving. Antenatal intervention theoretically reduces intraventricular pressure, improves coronary perfusion (which reduces ischemic damage), allows ventricular growth, and avoids induction of myocardial fibroelastosis, thus enabling improved functional postnatal repair. However, the exact timing of and selection of patients for such interventions remains unclear. Furthermore, in utero fetal cardiac intervention is still frequently bound by technical limitations, the often-late timing of diagnosis (20 weeks), and our current insufficient understanding of these diseases. Fetal valvuloplasty has become a fruitful area for intrauterine intervention, with indications including critical aortic and pulmonary stenosis or atresia, atrial septostomy for highly restrictive foramen ovale with aortic stenosis, and hypoplastic left heart syndrome (HLHS).
Technical success of the intracardiac procedure is defined as balloon inflation beyond the valve annulus, resulting in a broader jet through the valve as detected with Doppler ultrasound. Ideally, a successful procedure also leads to improved fetal circulation and to resolution of preexisting hydrops. Functional success consists of morphologic and hemodynamic evidence of increased ventricular and valvular growth, improved function, and continued patency of the valve or septum, potentially including regression of secondary damage. Demonstration of favorable morphology and good cardiac function also increases chances of successful postnatal surgery. Objective improvement of ventricular function and pulmonary venous Doppler wave forms can be documented [10].

Atrial Septostomy for Hypoplastic Left Heart Syndrome

Significant restriction of the atrial septum is found with 7% of transpositions of the great arteries and in 22% of patients with HLHS, and in 6% the atrial septum is completely closed.[11] This condition leads to increased pulmonary vein pressure and left atrial hypertension in utero, as well as to pulmonary venous arterialization and possibly hydrops. After birth, pulmonary venous return to the left atrium will be increased, and obstruction to pulmonary venous drainage will lead to a further rise in pulmonary pressure, with severe hypoxemia, pulmonary edema, and hemorrhage. On the other hand, a nonrestrictive foramen ovale is essential for successful correction of HLHS after birth, to avoid pulmonary congestion and allow oxygenation of the body. Therefore, prenatal detection of atrial septum restriction, with early delivery and early septostomy or surgery, improves outcome. Serial Doppler examination of the pulmonary arterial and venous return and detection of a high-velocity jet from left to right across the foramen ovale, which are indicative of raised left atrial pressure secondary to a restrictive foramen, may be used to select cases amenable to treatment in the prenatal period.
The experience with fetal balloon dilation is limited, and that with thermal septostomy is at best sporadic. The small second- or early third-trimester fetal atrium may limit the size of the balloon that can be used, and the small atrial wall is more prone to cardiac tamponade compared with ventricular puncture. The Boston group has reported technically successful balloon septostomy in six of seven cases to prevent hydrops in patients with HLHS.[12] The diameter of the achieved communication exceeded 2 mm in five out of seven cases. Perinatal mortality was comparable to what has been reported in larger series of postnatal surgical intervention. Alternatively, thermally induced defects appear to be too small and to close early. Overall, limited technical and functional success rates have been reported (in six of 17) [13].

Balloon Valvuloplasty for Hypoplastic Left Heart Syndrome
Because HLHS is a spectrum of left-sided cardiovascular malformations characterized by severe hypoplasia of the left ventricle and its outflow tract, approaches to therapy are necessarily multiple. The range of structural malformations includes critical aortic stenosis, unbalanced atrioventricular septal defects with hypoplasia of the left heart and aorta, severe aortal coarctation, and the association of atresia or hypoplasia of both the aortic and the mitral valve. These fetuses have a very small and less contractile left ventricle at birth that is unable to sustain the systemic circulation. The only available neonatal treatment is staged palliative surgery (Norwood operation, followed by a Fontan procedure). Overall 5-year survival is approximately 70%, and more than half of the survivors will require further surgery before the age of 5 years.

However, at mid-gestation, some HLHS fetuses have a somewhat normal sized left ventricle that appears dysfunctional against the outlet tract obstruction (aortic stenosis or severe coarctation), and they may be candidates for antenatal intervention. The best in utero predictors of poor outcome have been listed as little or no growth of the aortic and mitral valves, second-trimester left ventricular dilation, arrested growth of the left ventricle with reversed flow across the foramen ovale, and retrograde flow in the aortic arch [14].

The rationale for antenatal treatment is to prevent progression to a full-blown HLHS or left ventricular damage by the end of pregnancy. Successful interventions can improve right ventricular quality, which drives the univentricular circulation. To enable successful balloon deployment, an appreciable left ventricular size is required, which is clearly a limiting factor. Ventricular fibroelastosis is not a formal contraindication, because it can in some cases be resected after birth, but it may increase the risk for tamponade after withdrawal of instruments used in utero.

This intervention was first technically successful in 1991, and by 2000, 12 cases performed worldwide had been compiled. However, technical problems were frequent, with a 50% balloon rupture rate and a 75% incidence of bradycardia. Only two subjects survived, and one of them had a two-ventricle circulation after birth. Only the more extensive Boston experience learns what can be achieved after the learning curve. In their most recent series, 28 of 38 treated fetuses survived. From the initial 20 cases, there were 13 successful procedures between 21 and 29 weeks. Nevertheless, three died in utero after the procedure, one was born prematurely, and two patients opted for termination. Postprocedure assessments of the left heart showed growth of the ventricle, the mitral and aortic valve, and the ascending aorta. Of the seven born live, three were surviving with biventricular circulation, and the other had palliative surgery. Based on these data from technically successful procedures, one third will eventually have biventricular circulation, and occasionally postnatal interventions will be required [15].

Balloon Valvuloplasty for Pulmonary Atresia

Congenital critical pulmonary atresia with intact ventricular septum leads ultimately to hypoplasia of the right heart. The 5-year survival is only 64%, with only one third having biventricular circulation at the 10-year follow up. Cases with coronary fistulae are unsuitable for decompression after delivery, as they depend for their cardiac perfusion on the high pressure status.

Again, the rationale for treatment is preventing or delaying progression of ventricular hypoplasia, and to optimize right ventricular function, particularly when there is severe tricuspid regurgitation and hydrops. Combined scores based on tricuspid and pulmonary valve size, in combination with assessment of right atrial pressure, have been proposed as an aid in patient counseling and assessment. Reported technical success rates are high, and in some fetuses there was improved circulation and resolution of hydrops, allowing prolongation of pregnancy. However, it is uncertain if these results represent an improvement over the natural history [16].

Congenital Diaphragmatic Hernia (CDH)

CDH is a defect in the diaphragm which results from incomplete fusion of the embryonic structures that form the diaphragm. The main consequence of these condition is herniation of the abdominal organs into the chest cavity, which prevents normal pulmonary development and may result in lethal pulmonary hypoplasia at birth. Congenital diaphragmatic hernia occurs sporadically, with an incidence of 1 in 2500 to 1 in 5000 newborns, depending on whether stillbirths are included [17]. The main consequence of CDH is pulmonary hypoplasia, by a mechanism of external compression. Clinical features are: severe respiratory insufficiency, pulmonary hypertension, reduced surfactant. Although severe CDH can theoretically be diagnosed earlier, the condition is generally detected at 18 to 23 week anomaly scan. The standard sonographic section is the four-chamber view, in which the integrity of the lung parenchyma is evaluated.

The strategies for prenatal treatment of CDH are based on tracheal occlusion. As has been extensively proven in animal studies, tracheal occlusion accelerates pulmonary growth even exceeding the normal levels. Tracheal occlusion prevents tracheobronchial fluid from escaping the lungs and increases pressure of the lung fluid on the trachea bronchial tree and the pulmonary acini. External tracheal occlusion using tracheal clips placed by open surgery or endoscopy was attempted, but later discontinued because of its elevated aggressiveness. More recently, advanced in percutaneous fetoscopic techniques to achieve endotracheal occlusion by fetal tracheoscopy have resulted in a minimally invasive method with complication rates comparable to those associated with obstetric fetoscopy, thereby providing an acceptable alternative for fetal therapy [18].

Antenatal tracheal occlusion is now clinically applied by the fetal endoscopic tracheal occlusion (FETO) task force (fig.5). Under locoregional anesthesia through a 3.3-mm cannula and using fetoscopy, a balloon is inserted into the fetal trachea at 26 to 28 weeks and the occlusion is reversed in utero at 34 weeks [19]. This is much less invasive than earlier methods using tracheal clips or larger access cannulas [20]. In utero removal of the balloon can be done by either fetoscopy or ultrasound- guided puncture; however, emergency peripartum removal by laryngotracheoscopy or an EXIT procedure may be required if preterm labor ensues [21]. The European FETO task force has reported a survival rate of 50% to 57% in this group of fetuses with otherwise poor predicted survival [22]. No maternal complications were reported, but iatrogenic pPROM remains a major complication.

 

17 JPSS 8 1 2010-17

Figure 5.  The FETO procedure


More than 75% of patients have delivered beyond 34 weeks (mean gestational age at birth, 36 weeks), significantly later than the 31 weeks observed by Harrison and colleagues. Neonatal survival rate is higher with prenatal versus perinatal balloon retrieval (83.3% versus 33.3%; P = .013), a trend persisting until discharge (67% versus 33%; NS). Major predictors of survival are gestational age at delivery and lung size prior to FETO. In other words, fetuses with the smallest lungs are less likely to respond to fetal therapy than those with larger lungs. Apart from that, the individual increase in lung area or volume after FETO is an independent predictor of survival. Also, the pulmonary vascular reactivity changes following FETO are predictive. Trials are currently under design in Europe [23]. 

 

The quality of life of fetuses with diaphragmatic hernia varies substantially according to the series, but most authors agree that the large majority of survivors have an acceptable quality of life. The most common sequel is of course, respiratory insufficiency and particularly oxygen dependence, which may be present in up to 30% of cases, although generally with little of no clinical relevance. The available series are not large enough to estimate quality of life according to the prenatal parameters of severity. Except in the cases presenting within a syndrome, isolated CDH is almost always a sporadic malformation and therefore the risk of recurrence is extremely low [24].

Neural tub defects 

Neural tube defects (NTD) are a major source of mortality and morbidity. The 5-year mortality of neonatally repaired patients with spina bifida is 79 in 1000 births. Mortality can be as high as 35% among patients with symptoms of brainstem dysfunction, and 81% of children have hydrocephalus requiring treatment. More than 70% of NTD survivors have an IQ above 80, but only 37% can live independently as adults. The vast majority have anal sphincteric dysfunction and lower extremity paralysis [25].

Preliminary experience at Vanderbilt and Children’s Hospital of Philadelphia did not demonstrate improvement in outcome with intrauterine microsurgical closure of myelomeningocele compared with postnatal repair. These centers noted a decreased requirement for ventriculoperitoneal (VP) shunting, attributed in part to reversal of cerebellar herniation. Other potential outcomes, such as thinning of the corpus callosum and polymicrogyria, were not affected by in utero surgery. Fetal head size, typically lower after postnatal repair, has also been shown to increase, which is believed to be the result of restoration of cerebrospinal volume. The need for shunting among infants repaired in utero diminishes with passing time, and a number of them never require shunts. The combined experience suggests an approximately overall 30% (thus lower) incidence of VP shunting. This is clinically important, as the placing of a shunt increases the possibility of surgical complications and infection, thus affecting cognitive functioning in later life. Another important co-determinant of long-term outcome is the upper level of the lesion [26]. For each increase in vertebral level, the risk of receiving a shunt increases accordingly. A final determinant of outcome quality is the gestational age at repair: the shunt rate drops significantly, from 71% when fetal surgery is performed before 25 weeks, to 39% after that cutoff. Improvement in lower extremity function or urinary continence with in utero NTD repair has been more difficult to demonstrate. However, whereas postnatally repaired subjects have neurologic function that corresponds to the bony level of the defect, prenatally repaired subjects, who have maintained leg function in the prenatal period and had an early repair, have in the majority (57%) of cases a “better than predicted” leg function when evaluated over the short term.11 It is possible that these benefits are somehow compromised by tethered cord or inclusion cysts, which will require re-intervention. A major cognitive improvement of prenatally repaired fetuses is not expected [27]. An interesting observation was that in utero repairs showed a surprisingly impressive cosmetic result, confirming that fetal epithelial wound healing is more favorable. 

Open fetal surgery today has a measurable but acceptable maternal risk. Pulmonary edema has been observed, which is potentially reducible by improved tocolytic regimes. Transfusions are uncommon (2.2% in the Vanderbilt experience), and maternal bowel obstruction occurred in a single case. Preterm labor leading to delivery before 30 weeks occurs in approximately 10% to 15% despite aggressive tocolysis. Postoperative oligohydramnios is not uncommon but usually without significant clinical consequences, although occasional lethal fetal pulmonary hypoplasia has been observed. The risk of perinatal death at the time of surgery or associated with preterm delivery in the available studies was 3% to 6%.

Congenital Cystic Adenomatoid Malformation

Congenital cystic adenomatoid malformation is a common pulmonary malformation estimated to occur in approximately 1 in 3000 to 5000 pregnancies. CCAM is a dysplastic or hamartomatous tumor with overgrowth of terminal bronchioles and reduction of number of alveoli. It usually appears as a thoracic mass involving only one pulmonary lobe. In approximately 40% of patients, the CCAM may have a systemic vascular supply, similar to bronchopulmonary sequestration(BPS), and these forms are defined as hybrid CCAM-BPS. The classic pathologic classification as proposed by Stocker established three types [28].

When the CCAM is larger, additional study is warranted because of the risk of pulmonary compression and hydrops. Use of the ratio of the mass area to head circumference (CCAM volume ratio [CVR]) has been proposed as a prognostic measure, and it is gestational age independent. The CCAM volume (in milliliters) is sonographically measured by using the formula for an ellipse (length × height × width × 0.52). When CVR is higher than 1.6, an 80% risk for fetal hydrops is predicted. Sonographic follow-up frequency based on the CVR has been proposed, with weekly follow-up for CVR less than 1.2, twice a week for CVR 1.2 to 1.6, or even more for CVR greater than 1.6, but this protocol has not been validated. Cardiac function, placental thickness, and amniotic fluid volume should be measured. When the CVR is high late in pregnancy (>34 weeks) and respiratory distress is anticipated, EXIT procedure with lobectomy in a tertiary care center may be considered. Hydrops after viability should prompt delivery. Before 32 weeks, fetal intervention can be lifesaving, but no large series is available to judge among options. Percutaneous puncture and thoracoamniotic shunting of macrocystic masses have been reported, and both have the advantage of minimal invasiveness [29]. Wilson and associates recently reviewed their experience with 23 shunted cases at a mean gestational age of 21 to 22 weeks. The mean CVR in this group was 2.4, which fell to 0.7 after shunting. The mean interval between shunt and delivery was 11.8 weeks (36.3 weeks at birth).The overall survival was 74%, with one fetal and fi ve neonatal deaths, correlating with a shorter shunt-to-delivery interval. Thoracic deformation has been observed but seems uncommon. Several other case reports or smaller series have results in the same range.

Also, a recent systematic review came to the conclusion that cyst drainage improves perinatal survival among hydropic fetuses [30]. For solid lesions lobectomy via open fetal surgery can be considered. In a series of 22 cases operated between 21 and 31 weeks, there were 11 long-term survivors, and they were developmentally normal (up to 12 years of age) [31]. Hydrops resolved in 1 to 2 weeks, followed by normalization of the position of the mediastinum, and the remaining lung underwent impressive catch-up growth. Causes of fetal death despite fetal surgery were termination of pregnancy for Ballentyne syndrome, preterm labor and/or chorioamnionitis, and fetal hemodynamic compromise leading to intraoperative death in six fetuses and postoperative death in another two cases. To prevent intraoperative deaths, all prerequisites for fetal resuscitation, such as gaining access to the fetal circulation and appropriate monitoring techniques, should be foreseen. The use of prenatal steroids in complicated cases of CCAM may result in resolution of hydrops fetalis [32]. In a total of nine hydropic fetuses reported over three clinical series, resolution of hydrops was observed in all cases after maternal administration of betamethasone at dosages typically given for fetal maturation. The mechanism is unknown but it is postulated that steroids might accelerate lesion maturation or involution. In view of this, steroids might be used as a first-line therapy or medical adjunct in high-risk cases.

Lower urinary tract obstruction

Lower urinary tract obstruction (LUTO) is a descriptive term for a number of heterogeneous conditions that are relatively common (1 in 5000 to 8000 male neonates). Posterior urethral valves is by far the most common (at least one third in autopsy series), but other conditions such as stenosis of the urethral meatus, anterior valves, urethral atresia, ectopic insertion of a ureter, or (peri)vesical tumors give a similar clinical picture. LUTO leads to bladder distention, shaped to the level of the occlusion (keyhole sign), with compensatory hypertrophy and hyperplasia of bladder wall smooth muscle. Over time, compliance and elasticity decrease and may cause poor postnatal bladder function. Elevated bladder pressure prevents urinary inflow from above, and the ureterovesical angle may change, resulting in reflux hydronephrosis. Progressive pyelectasis and calyectasis compress the delicate renal parenchyma within the encasing serosal capsule, leading to functional abnormalities within the medullary and eventually the cortical regions. Focal compressive hypoxia probably contributes to the progressive fibrosis and perturbations in tubular function, resulting in the urinary hypertonicity that is observed. Eventually, this leads to renal insufficiency. Concurrently, amniotic fluid volume falls, and as a consequence—depending on gestational age—pulmonary hypoplasia evolves [33].

The prenatal evaluation of fetuses with the sonographic findings of LUTO must be comprehensive, and coexisting structural and chromosomal anomalies must be excluded before intervention can be considered. Female fetuses very often have more complex syndromes of cloacal malformations that do not necessarily benefit from in utero shunt therapy. Because of the presence of oligohydramnios or anhydramnios, karyotypes can be obtained by transabdominal chorionic villus or fetal blood sampling and through structural assessment of the fetus after amnioinfusion.

Vesicoamniotic shunts bypass the urethral obstruction, diverting the urine into the amniotic space and allowing drainage of the upper urinary tract and prevention of pulmonary hypoplasia and physical deformations by restoration of amniotic fluid volume. The type of urinary obstruction (postnatally diagnosed) was highly predictive of long-term renal outcome. Fetuses with posterior urethral valves have better outcomes than those with urethral atresia or the prune belly syndrome. Most children are developmentally normal, but some lag in growth, and pulmonary problems may persist in others. Among 18 survivors, six had acceptable renal function, four had mild insufficiency, and six required dialysis and transplantation [34].

Instead of conclusions – ethical dimensions of perinatal innovation

Medical and surgical innovations are often introduced into practice without adequate scientific and ethical evaluation. Fetal intervention and surgery has shared this history of unmanages innovation, but with impact on far fewer patients. The perinatal community should guide innovation in fetal intervention and surgery in an ethically responsible fashion [35]. The concept of the fetus as a patient is invaluable for innovation in perinatal medicine. The fetus is a patient when reliable links exist between it and its later achieving the moral status of a child and then person [36].But fetal surgery is also maternal surgery. This criterion reminds investigators that the willingness of a subject, in this case the pregnant women, to consent to risk does not establish whether the risk/benefit ratio is favorable. Investigators have an independent beneficence- based obligation to protect human subjects from unreasonably risky research and should use beneficence-based, risk-benefit analyses.

The phrase ”maternal-fetal surgery“ is useful if it reminds investigators of the need for such comprehensive analyses. If it is used to systematically subordinate fetal interests to maternal interest and rights, thus undermining the concept of the fetus as a patient in favour of the concept that the fetus is merely a part of the pregnant women, we reject this phrase. The most important conclusion, I think, for the maternal-fetal medicine specialists is that the moral status of fetal life cannot really be tackled in isolation from the moral value of maternal life and maternal autonomy. We cannot make the fetus our sole and primary focus and dismiss the mother, nor vice versa [37].

 

References 

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